The Role of Renal Interstitium in Kidney Development

肾间质在肾脏发育中的作用

• 批准号: 10445327
• 负责人: Thomas Joseph Carroll
• 金额: $ 70.42万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10445327
• 关键词: Ablation; Anatomy; Binding; Bioinformatics; Biological Assay; Biology; Cell Lineage; Cells; Cellular biology; Co-Immunoprecipitations; Complex; Data; Defect; Development; Distal; Duct (organ) structure; Endothelium; Enhancers; Epithelial; Fibroblasts; Gene Expression; Gene Expression Profile; Genes; Genetic Epistasis; Genetic Transcription; Heterogeneity; Histologic; In Situ Hybridization; Individual; Injury to Kidney; Kidney; Kidney Diseases; Knowledge; Ligands; Ligation; Location; Maintenance; Maps; Modeling; Molecular; Mus; Natural regeneration; Nature; Nephrons; Newborn Infant; Organ; Organoids; Pathway interactions; Pattern; Play; Population; Regulon; Renal Interstitial Cell; Research; Role; Signal Pathway; Signal Transduction; Testing; Tissue Engineering; Tissues; cell replacement therapy; cell type; gain of function; genome-wide; insight; interstitial; interstitial cell; mutant; nephrogenesis; notch protein; promoter; single cell analysis; single-cell RNA sequencing; transcription factor; transcriptome sequencing

Project Summary/Abstract The kidney is patterned along a cortical to medullary axis with specific segments of the nephron, collecting duct and vasculature all lying adjacent to each other in histologically distinct domains. In order for a kidney to function, different cell types from different cellular lineages must form at the same anatomical location. Although there has been some insight into how the individual lineages become patterned (such as proximal distal patterning of the nephron), how the different cell types/lineages coordinate their development resulting in the global patterning of the organ is unknown. We have recently found that the renal interstitial cells show extensive heterogeneity and patterning along the cortical/medullary axis of a newborn mouse kidney[1]. The patterned domains of the renal interstitium precisely map to the different anatomical domains within the kidney. How the different interstitial cell types arise and what role they play in kidney development/function are unknown. We hypothesize that the interstitium functions to relay and integrate signals from the different lineages and in turn, reinfources and integrates the differentiation of the renal parenchyma along the cortical/ medullary axis. Using bioinformatic analysis of single cell RNA-Seq data, we have identified unique transcriptional signatures for the different interstitial cell types. This information will allow us to understand how the pattern is established as well as its function. In this proposal, we will focus on the specification and function of a sub-population of interstitial cells we will refer to as the proximal tubule (PT) interstitium. In this proposal, we will investigate the mechanisms underlying specification of a subpopulation of renal fibroblasts we refer to as the proximal tubules interstitium (PT interstitium). Notch/Rbpj and Yap/Taz transcription factors are both active within this population and ablation of either pathway using Foxd1Cre has revealed overlapping roles in the specification of this cell type. Our preliminary analysis indicates that the PT interstitium is necessary for the maturation of the adjacent proximal tubules. We hypothesize that the PTs and/or endothelia produce Notch/Rbpj and Yap/Taz activators and that cells with overlapping pathway activation become PT intersitium. The PT interstitium produces signals that promote the differentiation/maturation of the PTs. This crosstalk allows the co-maturation and integration of the proximal tubules and other cortical cell types. We further hypothesize that disruption of normal cortical-medullary pattern in renal organoids leads to defects in Yap/Taz and/or Notch/Rbpj signaling and contributes to the lack of nephron maturation in these tissues. These hypotheses will be tested here. Completion of these aims will open up an entirely new field of kidney interstitial biology that will have a long and lasting impact on the multiple fields including kidney development, kidney disease, tissue engineering and kidney injury/regeneration.

项目总结/摘要 肾脏沿着皮质到髓质轴与肾单位的特定节段形成图案， 集合管和脉管系统都在组织学上不同的区域中彼此相邻。为了使 肾脏要发挥功能，来自不同细胞谱系的不同细胞类型必须在相同的解剖结构上形成。 位置.尽管已经有一些关于个体血统如何形成模式的见解（例如 肾单位的近端远端模式），不同的细胞类型/谱系如何协调它们的发育 导致器官的整体模式是未知的。 我们最近发现，肾间质细胞表现出广泛的异质性和模式， 沿着新生小鼠肾脏的皮质/髓质轴[1]。肾间质的模式域 精确地映射到肾脏内的不同解剖区域。不同类型的间质细胞 它们在肾脏发育/功能中起什么作用是未知的。我们假设 氚的功能是传递和整合来自不同谱系的信号， 并整合了肾实质沿着皮质/髓质轴的分化。使用 通过对单细胞RNA-Seq数据的生物信息学分析，我们已经确定了用于单细胞RNA-Seq的独特转录特征。 不同的间质细胞类型。这些信息也将使我们了解模式是如何建立的 作为其功能。在本提案中，我们将重点关注间质细胞亚群的规格和功能。 我们称之为近曲小管（PT）肾小管。 在这个建议中，我们将研究肾细胞癌亚群的特异性表达的机制。 成纤维细胞，我们称之为近端肾小管（PT肾小管）。Notch/Rbpj和雅普/塔兹 转录因子在该群体中都是活跃的，并且使用Foxd 1Cre的任一途径的消融具有 揭示了在这种细胞类型的规范中的重叠作用。我们的初步分析表明， 肾小管是邻近近端小管成熟所必需的。我们假设PT 和/或内皮细胞产生Notch/Rbpj和雅普/Taz激活剂，具有重叠途径细胞 激活成为PT intersitium。PT间质产生信号，促进 PT的分化/成熟。这种串扰允许近端细胞的共成熟和整合。 小管和其他皮质细胞类型。我们进一步假设正常皮质-髓质模式的破坏 在肾类器官中的表达导致雅普/Taz和/或Notch/Rbpj信号传导的缺陷，并有助于缺乏 这些组织中的肾单位成熟。这些假设将在这里得到验证。这些目标的实现将开启 这是一个全新的肾间质生物学领域，将对多种疾病产生长期持久的影响。 包括肾脏发育、肾脏疾病、组织工程和肾脏损伤/再生。